Our recent studies have identified a novel genetic variation associated with age-related macular degeneration (AMD). The 4917G allele of mitochondrial DNA (mtDNA) was independently associated with AMD (OR=3.30, 95% CI 1.25 - 7.17, p=0.01) following adjustment for known risk factors including complement factor H, LOC387715 gene on chromosome 10q26, age, gender and smoking status. The 4917G polymorphism is a common variation in haplogroup T mitochondria and results in a non-synonomous change, asparagine for aspartic acid, in the ND2 subunit of Complex I. Mitochondria play essential roles in controlling cellular energy production, apoptosis and redox homeostasis. Mutations and polymorphisms of the mitochondrial genome often lead to pathological lesions in tissues with high energy demand, such as the retina. The retinal pigment epithelium (RPE) is a primary site of lesion in AMD. Accumulating evidence indicates that oxidative stress induced dysfunction of the RPE contributes to the development and progression of AMD. We hypothesize that specific polymorphisms in the mitochondrial genome control susceptibility to oxidative injury in the RPE. The hypothesis will be tested in the following two specific aims using cultured human fetal RPE cells which do not carry somatic damage to the mtDNA seen with aging. Specific Aim 1 will determine whether specific mitochondrial DNA polymorphisms are associated with increased susceptibility to oxidant-induced apoptosis in cultured fetal RPE cells and whether the sensitivity is associated with mitochondrial genetic variations. Specific Aim 2 will determine whether variations in the mitochondrial genome affect responses to agents that induce the antioxidant responses in the RPE. Results from these studies will support the use of mtDNA haplotypes as a genetic biomarker in identifying people with increased risk of AMD and may lead to predictors of the outcome of clinical treatment with antioxidant supplementation or other agents that augment the antioxidant defense of the retina. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Recent studies have identified that the risk of developing AMD is associated with a novel genetic variation in the mitochondrial genome. Characterization of the functional consequences of such variation will be the focus of the current proposal.